title: Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor.
abstract: The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK(I) = 7.3-7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.
authors.affiliation: Cardiovascular Metabolic Research, Johnson and Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. tbarret1@its.jnj.com
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Barrett
authors.forename: Heather L
authors.initials: HL
authors.lastname: Palomino
authors.forename: Theresa I
authors.initials: TI
authors.lastname: Brondstetter
authors.forename: Kimon C
authors.initials: KC
authors.lastname: Kanelakis
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Peter V
authors.initials: PV
authors.lastname: Haug
authors.forename: Wen
authors.initials: W
authors.lastname: Yan
authors.forename: Andrew
authors.initials: A
authors.lastname: Young
authors.forename: Hong
authors.initials: H
authors.lastname: Hua
authors.forename: Juliet C
authors.initials: JC
authors.lastname: Hart
authors.forename: Da-Thao
authors.initials: DT
authors.lastname: Tran
authors.forename: Hariharan
authors.initials: H
authors.lastname: Venkatesan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rosen
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Peltier
authors.forename: Kia
authors.initials: K
authors.lastname: Sepassi
authors.forename: Michele C
authors.initials: MC
authors.lastname: Rizzolio
authors.forename: Scott D
authors.initials: SD
authors.lastname: Bembenek
authors.forename: Tara
authors.initials: T
authors.lastname: Mirzadegan
authors.forename: Michael H
authors.initials: MH
authors.lastname: Rabinowitz
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Shankley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: C559853:1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011720:Pyrazoles; D011393:Procollagen-Proline Dioxygenase